Methods and systems for therapeutic neuromodulation

ABSTRACT

Systems, methods and computer-readable media are disclosed for providing therapeutic auditory stimulation. Consistent with disclosed embodiments, a system for providing therapeutic auditory stimulation may comprise a diagnostic unit that computes an EEG spectral density of a patient and a heart rate spectral density of a patient and provides values for one or more EEG frequency bands and one or more heart rate frequency bands. The system may also comprise a therapy unit that generates, based on the provided values, one or more stimulation waveforms corresponding to one or more of the EEG frequency bands and provides the stimulation waveforms for therapeutic auditory stimulation. The stimulation waveforms may comprise audible carrier frequencies modulated by signals with frequencies that vary exponentially with time. The EEG frequency bands may comprise the delta, theta, alpha, beta 1, beta 2, and gamma EEG frequency hands.

The present application claims the benefit of priority to U.S.Provisional Patent Application No. 62/115,095, filed Feb. 11, 2015, thecontents of which are hereby incorporated by reference herein in theirentirety.

TECHNICAL FIELD

The disclosed embodiments generally relate to systems, methods, andcomputer-readable media for treating physiological and psychologicaldisorders using auditory neuromodulation.

BACKGROUND

Stress can evoke a hypothalamic response, causing the release ofhormones that in turn activate the hypothalamic-pituitary-adrenal (HPA)axis, which is involved in regulating emotions, metabolism, cognition,and the immune system. This in turn evokes a stress response which maydisrupt blood sugar levels, suppress immune and inflammatory responses,interfere in memory formation, and disrupt feedback mechanisms intendedto inhibit further stress responses. Chronic stress may result inimpaired mental and physical health.

Existing medical treatments may have negative systemic side effects,while surgical treatments may be destructive and invasive. However,sound may be used to encode neural signals for therapeutic effect. Suchauditory neuromodulation has been used to treat disorders in humans. Forexample, multiple studies have demonstrated that auditoryneuromodulation may significantly decrease tinnitus. Tass, P. A.,Adamchic, I., Freund, H. J., von Stackelberg, T., Hauptmann, C. (2012),“Counteracting tinnitus by acoustic coordinated reset neuromodulation.”Adamchic, I., Hauptmann, C., Tass, P. A. (2012), “Changes of oscillatoryactivity in pitch processing network and related tinnitus relief inducedby acoustic CR neuromodulation.” Silchenko, A. N., Adamchic, I.,Hauptmann, C., Tass. P. A. (2013), “Impact of acoustic coordinated resetneuromodulation on effective connectivity in a neural network of phantomsound.” This subjective decrease in tinnitus may be accompanied bymodification of abnormal EEG rhythms. Adamchic, I., Toth, T., Hauptmann,C., Tass, P. A. (2013). “Reversing pathologically increased EEG power byacoustic coordinated reset neuromodulation.” In a rat model ofantidepressant-like activity, treatment with auditory neuromodulationdemonstrated effects similar to traditional chemical anti-depressants.Izvarina N. L., Lensman M. V., Murovets V. O., Savoxin A. A,“Antidepressant activity of Acoustical Neuro-Modulation in comparisonwith well-known antidepressants in forced swim test in rats”International Journal of Psychophysiology 69:3, September 2008, p. 288;Isvarina N. L., Lensman M. V., Murovets V. O., Savoxin A. A.,“Investigation of antidepressants activity of sound beats created withdifferent algorithms of modulation in comparison with antidepressants inforced swim test (FST) on rats.” Poster, 8^(th) IBRO World Congress ofNeuroscience/Florence-Italy Jul. 14-18, 2011. A493.

Standard methods of auditory neuromodulation may only achieve temporaryresults, as the patient may quickly accommodate to the auditorystimulation. Consequently, there exists a need for systems and methodsfor providing long-term treatment of physiological and psychologicaldisorders using auditory neuromodulation. The envisioned embodimentssatisfy this need by providing therapeutic nonlinear, multi-parametricmodulation of sound. This therapeutic auditory stimulation mayselectively influence the activation of the HPA axis, modulating therelease of neurotransmitters to influence psychological andphysiological behavior. Thus this therapeutic auditory stimulation maybe used to treat anxiety disorders, autism spectrum disorders, and otherpsychological and physiological disorders described herein.

SUMMARY

The disclosed embodiments include, for example, systems and methods forproviding therapeutic auditory stimulation. This therapeutic auditorystimulation may complement or provide an alternative to medication,behavioral therapy, or other medical interventions for treatment ofabnormal physiological states, including autism spectrum disorders;anxiety; post-traumatic stress disorders; depressive disorders,including depression presenting in patients with a history ofpost-traumatic pain; phantom pain disorders; multi-infarct dementia(Alzheimer-type vascular dementia); memory loss; mental confusion;Parkinson's disease; multiple personality disorders; headache andmigraine; high blood pressure; and constipation. Additionally, andwithout limitation, abnormal physiological states may include type 2diabetes, and treatment with therapeutic auditory stimulation may beused to reduce overall morbidity, improve quality of life, and decreasevariations in blood glucose levels. Additionally, and withoutlimitation, abnormal physiological states may include infant cerebralpalsy, stuttering, psychosomatic disorders, and coma. In someembodiments, therapeutic auditory stimulation may be provided to apregnant women as a preventive measure to decrease the likelihood ofsubsequent abnormal physiological states in her developing fetus. Forexample, therapeutic auditory stimulation may be provided to a pregnantwomen as a preventive measure to decrease the subsequent likelihood ofautism spectrum disorders; anxiety; post-traumatic stress disorders;depressive disorders; and similar disorders in her developing fetus.

The disclosed embodiments may include, for example, a device forproviding therapeutic auditory stimulation. The device may include aprocessor and a non-transitory memory. The memory may containinstructions that when executed by the processor cause the device togenerate one or more stimulation waveforms. These stimulation waveformsmay correspond to electroencephalographic (EEG) frequency bands. Theymay comprise an audible carrier frequency modulated by signals withfrequencies that vary non-linearly with time. The device may alsoinclude means for providing one or more of the stimulation waveforms toa patient as therapeutic auditory stimulation. For example, the devicemay include local means for providing the signal, including electronicdevices such as music players, computers, or smartphones. As anadditional example, local means for providing the signal may includemedical products, such as special purpose therapeutic devices. Theproviding means may also include remote means for providing the signal.Remote provide means may comprise means for storing and transmitting thestimulation signal so that the generation of stimulation signal may betemporally or spatially separated from the provision of the stimulationsignal. Storage means may include non-transitory computer-readablemedia, such as magnetic tape or magnetic disks, optical disks, flashmemory, or read-only memory. Transmission means may include computernetworks, telephone networks, or the physical transmission of the abovestorage media.

In certain embodiments, EEG frequency bands may include a low-frequencyband and a high-frequency band. The stimulation waveform correspondingto the low-frequency band may be provided before the stimulationfrequency corresponding to the high frequency band. In certainembodiments, the stimulation waveform corresponding to thehigh-frequency band may be provided before the stimulation frequencycorresponding to the low frequency band.

In certain embodiments, the stimulation waveforms may comprise pairs offrequency intervals, the pairs including increasing frequency intervalsand decreasing frequency intervals, the modulating signal frequenciesincreasing exponentially during the increasing frequency intervals anddecreasing exponentially during the decreasing frequency intervals. Insome embodiments, the durations of the pairs may vary non-linearly. Insome embodiments, the durations of the decreasing frequency intervalsmay exceed durations of the increasing frequency intervals. In someembodiments, the durations of the frequency intervals may beapproximately related by a constant multiple. This constant multiple maybe the golden ratio.

In certain embodiments, the EEG frequency bands may be selected from thegroup consisting of the delta, theta, alpha, beta 1, beta 2, and gammaEEG frequency bands.

The disclosed embodiments may also include, for example, a system forproviding therapeutic auditory stimulation. This system may include adiagnostic unit configured to compute an EEG spectral density and aheart rate spectral density of a patient. The unit may provide valuesfor one or more EEG frequency bands and one or more heart rate frequencybands. The system may include a therapy unit that generates, based onthe values provided by the diagnostic unit, one or more stimulationwaveforms corresponding to one or more of the EEG frequency bands. Thetherapy unit may provide the stimulation waveforms for therapeuticauditory stimulation.

In certain embodiments, the diagnostic unit may include anelectroencephalograph comprising two or more occipital electrodes. Incertain embodiments the diagnostic unit may calculate the sympathovagalbalance of the patient. In some embodiments, the stimulation waveformsmay comprise audible carrier frequencies modulated by signals withfrequencies that vary exponentially with time. In various embodiments,the modulating signal frequencies may increase exponentially from thebeginning to the end of each stimulation waveform. In some embodiments,the stimulation waveforms may comprise pairs of frequency intervals. Thepairs may include increasing frequency intervals and decreasingfrequency intervals. The modulating signal frequencies may increaseexponentially during the increasing frequency intervals and decreasingexponentially during the decreasing frequency intervals. The durationsof the pairs may vary non-linearly. The durations of the decreasingfrequency intervals may exceed durations of the increasing frequencyintervals. The durations of frequency intervals may be approximatelyrelated by a constant multiple. The constant multiple may be the goldenratio.

In some embodiments, the EEG frequency bands may comprise the delta,theta, alpha, beta 1, beta 2, and gamma EEG frequency bands. In someembodiments, the stimulation waveforms may be generated remotely fromthe therapeutic auditory stimulation. In certain embodiments, the firststimulation waveform may be provided for therapeutic auditorystimulation telephonically.

The disclosed embodiments may include, for example, a method forproviding therapeutic auditory stimulation. The method may comprisereceiving an indication of an abnormal physiological state of a patient.The method may comprise generating a first stimulation waveform based onthe indication. The first stimulation waveform may correspond to a firstEEG frequency band. The first stimulation waveform may comprise anaudible carrier frequency modulated by a first signal with anexponentially varying frequency. The method may comprise providing thefirst stimulation waveform for first therapeutic auditory stimulation.

In certain embodiments, a maximum frequency of the first signal maycorrespond to a maximum frequency associated with the first EEGfrequency band. In some embodiments, the method may further comprisegenerating a second stimulation waveform based on the indication. Thesecond waveform may correspond to a second tEG frequency band and maycomprise an audible carrier frequency modulated by a second signal withan exponentially varying frequency. The method may further compriseproviding the second stimulation waveform for second therapeuticauditory stimulation.

In certain embodiments, the duration of the increasing frequencyinterval and the decreasing frequency interval may depend on the firstEEG frequency band. In some embodiments, the indication may be based onelectroencephalography and sympathetic-vagal balance measurement of thepatient. In various embodiments, the first stimulation waveform may beprovided for first therapeutic auditory stimulation on acomputer-readable medium.

The disclosed embodiments may include, for example, a method forproviding therapeutic auditory stimulation. The method may includemeasuring, using a portable electroencephalograph, the sympathovagalbalance of a patient and the contributions from one or more EEGfrequency bands to an EEG of the patient. The method may also includegenerating a train of stimulation waveforms. The train of stimulationwaveforms may be based on an indication of an abnormal physiologicalstate of a patient. One of the stimulation waveforms may correspond toan EEG frequency band and may comprise an audible carrier frequencymodulated by a signal. The signal may include frequency intervalscomprising increasing frequency intervals during which the frequency ofthe signal increases exponentially. The frequency intervals may comprisedecreasing frequency intervals during which the frequency of the signaldecreases exponentially. The durations of the increasing frequencyintervals and the decreasing frequency intervals may vary and may dependon the EEG frequency band corresponding to the stimulation waveform. Themethod may comprise providing the stimulation waveforms to an audiospeaker for generating therapeutic auditory stimulation for the patient.

In certain embodiments, the train of stimulation waveforms may begenerated remotely from the audio speaker. In various embodiments, themethod may further comprise storing the train of stimulation waveformsin a non-transitory memory before providing the stimulation waveforms tothe audio speaker. In some embodiments, a telephone may comprise theaudio speaker.

The disclosed embodiments may include, for example, a computer-readablemedium comprising instructions that cause a computer to perform theoperations for providing therapeutic auditory stimulation. Theoperations may comprise generating a train of stimulation waveformsbased on an indication of an abnormal physiological state of a patient.One of the stimulation waveforms may correspond to an EEG frequency bandand may comprise an audible carrier frequency modulated by a signal. Thesignal may include frequency intervals comprising increasing frequencyintervals during which the frequency of the signal increasesexponentially and decreasing frequency intervals during which thefrequency of the signal decreases exponentially. The duration of thefrequency intervals may be related by an approximately constantmultiple.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the disclosed embodiments, as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings are not necessarily to scale or exhaustive. Instead,emphasis is generally placed upon illustrating the principles of theinventions described herein. The accompanying drawings, which areincorporated in and constitute a part of this specification, illustrateseveral embodiments consistent with the disclosure and together with thedescription, serve to explain the principles of the disclosure. In thedrawings:

FIG. 1 depicts an exemplary electronic device for providing therapeuticstimulation.

FIG. 2A depicts an exemplary classification of the EEG power spectruminto frequency bands.

FIG. 2B depicts an exemplary transformation of a heart rate signal intothe frequency domain.

FIG. 2C depicts the effect of therapeutic auditory stimulation in amodel of depression.

FIG. 3 depicts a block diagram illustrating an exemplary system forproviding therapeutic auditory stimulation.

FIG. 4A depicts a block diagram illustrating an exemplary diagnosticunit for receiving indications of the condition of a patient.

FIG. 4B depicts an exemplary schematic of an electrode placementarrangement for quantitative or LORETA EEG.

FIG. 4C depicts an exemplary illustration of the use of quantitative orLORETA EEG to localize a region of abnormal neural activity fordiagnostic and monitoring purposes.

FIG. 5 depicts a block diagram illustrating exemplary functionalcomponents of a therapy unit.

FIG. 6A depicts an exemplary method for providing therapeutic auditorystimulation.

FIG. 6B depicts an exemplary user interface for providing therapeuticauditory stimulation.

FIGS. 7A-7D depict characteristics of exemplary waveforms fortherapeutic auditory stimulation.

FIGS. 8A-8D) depict exemplary pre-treatment and post-treatmentneuroimages obtained using LORETA EEG that illustrate the effect oftherapeutic auditory stimulation on abnormal neural activity.

DETAILED DESCRIPTION

Consistent with disclosed embodiments, the envisioned therapeuticauditory stimulation may be used to treat autism spectrum disorders;anxiety; post-traumatic stress disorders; depressive disorders,including depression presenting in patients with a history ofpost-traumatic pain; phantom pains disorders; multi-infarct dementia(Alzheimer-type vascular dementia); memory loss; mental confusion;Parkinson's disease; multiple personality disorders; headache andmigraine; high blood pressure; and constipation. In patients with type 2diabetes, therapeutic auditory stimulation may be used to reduce overallmorbidity, improve quality of life, and decrease variations in bloodglucose levels. Therapeutic stimulation may be used to treat infantcerebral palsy, stuttering, psychosomatic disorders, and coma. In someembodiments, therapeutic auditory stimulation may be provided to apregnant women as a preventive measure to decrease the likelihood ofsubsequent abnormal physiological states in her developing fetus. Forexample, therapeutic auditory stimulation may be provided to a pregnantwomen as a preventive measure to decrease the subsequent likelihood ofAutism spectrum disorders; anxiety; post-traumatic stress disorders;depressive disorders; and similar disorders in her developing fetus.

FIG. 1 depicts an exemplary electronic device for providing therapeuticstimulation, consistent with disclosed embodiments. This electronicdevice may comprise exemplary computing system 100. In some embodiments,system 100 may include a processor 105 and a non-transitory memory 110.In certain embodiments, system 100 may (but need not) include one ormore of a display 115, I/O interface(s) 120, and network adapter 125.These units may communicate with each other via bus 130 and/orwirelessly, or a combination thereof. In various embodiments, processor105 may be one or more microprocessors or central processor units (CPUs)performing processing operations. Memory 110 may be a volatile ornon-volatile, magnetic, semiconductor, tape, optical, removable,non-removable, or other type of storage device or tangible (i.e.,non-transitory) computer-readable medium. In various embodiments, memory110 may store data 140 reflecting any type of information in any formatthat the system may use to perform operations consistent with thedisclosed embodiments. Memory 110 may store instructions 135 to enableprocessor 105 to execute one or more applications, including program(s).Alternatively, the instructions, application programs, etc., may bestored in an external storage in communication with server(s) via anetwork. Display 115 may be any device which provides a visual output,for example, a computer monitor, an LCD screen, etc. I/O interface 120may include, for example, a keyboard, a mouse, an audio input device, atouch screen, or an infrared input interface. Network adapter 125 mayenable device 100 to exchange information with external networks. Invarious embodiments, network adapter 125 may include a wireless widearea network (WWAN) adapter, or a local area network (LAN) adapter.Consistent with disclosed embodiments, the components shown in FIG. 1may reside in a single device or multiple devices.

FIG. 2A depicts an exemplary classification of the EEG power spectruminto frequency bands. An electroencephalogram is a recording of theelectrical activity of a patient's brain. Both the time domain and thefrequency domain representation of the EEG signal may be of diagnosticvalue. The power spectrum of the EEG signal may be divided into distinctbands. These bands may be even spaced on a logarithmic scale, meaningthat the frequencies defining a band are approximately fixed multiplesof the frequencies defining the preceding band. As an illustrativeexample, the upper frequency for alpha waves (13 Hz) may beapproximately 1.7 times the upper frequency for theta waves (8 Hz),which in turn may be approximately 1.75 times the upper frequency forthe delta wave band (5 Hz). The fixed multiple may approximate thegolden ratio (φ), an irrational number. Functionally, this relationshipreduces entraimnent and cross-talk between signals in the differentfrequency bands.

One of ordinary skill in the art would recognize that othercategorizations of EEG power spectral density, differing in number orarrangement of bands, are possible. The categorization illustrated inFIG. 2A includes alpha, beta 1, beta 2, gamma, delta, and theta bands.Though this categorization includes minimum and maximum frequencies,those frequencies do not define the bands. Instead, the bands correspondto mental states or processes and are defined with reference to thoseprocesses. As used herein, when two bands are considered, thehigh-frequency band may have a higher maximum frequency, and thelow-frequency band may have a lower minimum frequency. In certainaspects, the high-frequency band and the low frequency band may bedistinct. For example, when an alpha band and a beta band areconsidered, the beta band is the high-frequency band and the alpha bandis the low-frequency band. When a beta band and a theta band areconsidered, the beta band is the high-frequency band and the theta bandis the low-frequency band.

Gamma waves are patterns of neural oscillation corresponding to highermental activity, such as perception, problem solving and emotions, andconsciousness. In some embodiments, gamma waves may be defined asencompassing waves with frequencies ranging from 25-100+ Hz. Morepreferably, gamma waves may be defined as encompassing waves withfrequencies ranging from 34-55 Hz.

Beta waves are patterns of neural oscillation corresponding to active,busy, or conscious thinking. Beta waves may correspond to activeconcentration, arousal, and cognition. In some embodiments, beta wavesmay be defined as encompassing waves with frequencies ranging from 13-34Hz. More preferably, Beta 1 waves may be defined as encompassing waveswith frequencies ranging from 13-21 Hz and Beta 2 waves may be definedas encompassing waves with frequencies ranging from 22-34 Hz.

Alpha waves are patterns of neural oscillation corresponding to awakerelaxation and pre-awake or pre-sleep drowsiness. In some embodiments,alpha waves may be defined as encompassing waves with frequenciesranging from 8-13 Hz.

Theta waves are patterns of neural oscillation corresponding to deepmeditative, drowsy, or dreaming states. Strong or persistent theta wavesmay indicate brain pathologies. In some embodiments, theta waves may bedefined as encompassing waves with frequencies ranging from 5-8 Hz.

Delta waves are patterns of neural oscillation corresponding todreamless sleep with loss of body awareness. In some embodiments, thetawaves may be defined as encompassing waves with frequencies ranging from3-5 Hz.

Consistent with disclosed embodiments, abnormal mental states may beidentified using EEGs. For example, anxiety or depression may beindicated by increased power in the alpha and beta EEG bands. As anadditional example, patients with attention deficit disorder may presentwith increased power in theta EEG bands and an increase in the beta EEGband as compared to the gamma EEG band. As described below, altering thepower in EEG bands may have therapeutic effect. For example, increasingand decreasing the contribution of the alpha EEG band may provide atreatment for anxiety.

FIG. 2B depicts an exemplary transformation of a heart rate signal intothe frequency domain, consistent with disclosed embodiments. In someembodiments this transformation may be a heart rate power spectraldensity. In certain aspects, the interval between heartbeats may reflectnervous system activity, such as autonomic nervous system activity,affecting the heart rate. For example, this interval may depend on thebalance between sympathetic and vagal activation of the heart (i.e. thesympathovagal balance). Abnormal sympathetic or vagal activation mayindicate an abnormal physiological state, such as an abnormal mentalstate. As a non-limiting example, abnormal activation may indicateanxiety, depression, panic disorders, post-traumatic stress disorders,autism spectrum disorders, or other disordered mental states as known byone of skill in the art. Time domain statistics, such as the standarddeviation of the heart rate interval or the mean-squared differencebetween successive heart rate intervals may indicate abnormal nervoussystem activity. Frequency domain statistics, such as contributions tothe power spectral density of the heart rate interval, may also indicateabnormal nervous system activity. For example, FIG. 2B depicts the lowand high frequency components of the power spectral density of heartbeatinterval times. As described below, the magnitude of the components maybe computed using various techniques known to one of skill in the art.The low frequency component of the power spectral density may beassociated with fluctuations in sympathetic nerve activity. The highfrequency component may be associated with fluctuations of vagal-cardiacnerve activity. The ratio of the low frequency component to the highfrequency component may indicate the relative contributions ofsympathetic and parasympathetic autonomic nervous system components tothe heart rate. Abnormalities in this balance may indicate abnormalmental states and can be used as diagnostic criteria in selectingappropriate therapeutic auditory stimulation.

Consistent with disclosed embodiments, therapeutic auditory stimulationmay provide auditory signals comprising certain waveforms correspondingto different EEG bands. As discussed below with respect to FIGS. 7A-7D,the stimulation waveforms may vary non-linearly in duration, frequency,and rate of change of frequency. The correspondence between astimulation waveform and an EEG band may be functional. For example,providing the stimulation frequency may affect the contribution of thatEEG band to the overall power spectrum of the EEG. In some aspects, thecontribution may be reduced. This functional relationship may be basedon a correspondence between frequency parameters of the stimulationwaveform and the frequency parameters of the corresponding EEG bands.

As described, in response to the therapeutic auditory stimulation, thecontribution from corresponding EEG bands may change. This change may atleast temporarily persist once the external stimulation is removed.Consistent with disclosed embodiments, therapeutic mental or behavioralchanges may arise from this change. In some embodiments, some commonmechanism may generate both the observed change in EEG contributions andthe therapeutic mental or behavioral changes. For example, providingtherapeutic stimulation corresponding to the alpha EEG band describedabove may cause a decrease in the contribution of the alpha EEG band.This decrease may cause, or be associated with, an increase in alertnessand a reduction in symptoms of depression.

Envisioned systems and methods may use a perceptible carrier signal toprovide otherwise imperceptible signals, consistent with disclosedembodiments. In some embodiments, the perceptible carrier signal may bean audible carrier signal. In certain aspects, this audible carriersignal may include audible carrier frequency waveforms. For example, theauditory frequency range may be considered to extend approximately from20 Hz to 20 kHz. Therapeutic auditory stimulation corresponding toalpha, theta, delta, or similar brain waves may be provided using acarrier wave at an audible carrier frequency modulated by a modulatingsignal corresponding to the targeted EEG band. While therapeuticauditory stimulation is disclosed in this application, one of skill inthe art would recognize that the same disclosed stimulation signalscould be used to provide other forms of therapeutic stimulation suitablefor other sensory organs. For example, the disclosed stimulation signalscould be provided to the eyes of the patient using light as visualtherapeutic stimulation, or to the skin using pressure, heat, orelectrical stimulation as tactile therapeutic stimulation. Whileamplitude modulation of the perceptible carrier signal is disclosed inthis embodiment, the form of modulation depends only on the targetedsensory organ and may include any one or more of amplitude, frequency,phase, or other signal characteristics known to one of skill in the art.

Envisioned systems and methods may use stimulation signals with multiplenon-linear aspects, consistent with disclosed embodiments. Thesenon-linear aspects may include non-linear changes in modulating signalfrequency, amplitude, phase, or other signal characteristics known toone of skill in the art. These changes may occur at rates and over timedurations that also vary in a non-linear manner. In some embodiments,these non-linear aspects of the stimulation signals may enhance theeffect of the therapeutic signal. For example, these non-linear aspectsof the signal may prevent accommodation by the nervous system of thepatient to the therapeutic stimulation.

FIG. 3 depicts a block diagram of an exemplary system for providingtherapeutic auditory stimulation consistent with disclosed embodiments.According to some embodiments, the exemplary system may comprise adiagnostic unit 310 and a therapy unit 330. In some embodiments, asingle device may comprise diagnostic unit 310 and therapy unit 330. Incertain embodiments, therapy unit 330 may comprise one or more devicesdistinct from diagnostic device 310. For example, diagnostic unit 310may comprise a potable EEG device and therapy unit 330 may comprise acomputing device controlling an audio output. For example therapy unit330 may comprise a music player, mobile device, tablet computer, laptopcomputer, special purpose PC card (e.g. PC, PCMCIA, ExpressCard, orsimilar modules), desktop computer, or server. The audio output maycomprise one or more speakers and/or headphones. In some embodiments,the computing device may be configured with special purposeinstructions. In certain aspects, these special purpose instructions mayconfigure the computing device to perform one or more of the functionsof generating therapeutic auditory stimulation, analyzing EEG and/orheart rate variability signals, and managing stored therapeutic auditorystimulation waveforms. In some aspects, the stored waveforms may bestored in European Data Format (edf) files. In some embodiments,elements of the disclosed exemplary system may comprise electronicdevices as described with reference to FIG. 1.

Diagnostic unit 310 may receive indications of the condition of apatient, consistent with disclosed embodiments. In certain embodiments,diagnostic unit 310 may process these indications, transforming them toenable diagnosis of a condition. In certain embodiments, a user maydetermine appropriate therapeutic auditory stimulation based on theprocessed indications. In various embodiments, the diagnostic unit mayautomatically determine, using a processor, appropriate therapeuticauditory stimulation based on the processed indications. For example,diagnostic unit 310 may use a processor to access a lookup table storedin a memory to determine appropriate therapeutic auditory stimulation.As an additional example, diagnostic unit 310 may use a processor toimplement a decision tree or a learning algorithm, such as a machinelearning algorithm, to determine appropriate therapeutic auditorystimulation. Other methods of automatically determining therapeuticstimulation based on processed patient data may also be used, as wouldbe known by one of skill in the art.

Diagnostic unit 310 may comprise a signal conditioning unit and a signalprocessing unit, consistent with disclosed embodiments, as describedbelow with reference to FIG. 4. These units may comprise one or moreelectronics devices. For example, consistent with disclosed embodiments,a special-purpose computer, such as an EEG machine, may comprise one ormore of the signal conditioning and signal processing units. In someembodiments, the EEG machine may portable. For example, the EEG machinemay be less than or comparable to a laptop computer in dimension andweight. In certain embodiments a general-purpose computer such as aworkstation, desktop, laptop, smartphone, tablet computer or similarcomputing device comprise one or more of the signal conditioning andsignal processing units, in combination with one or more additionaldata-acquisition components.

Therapy unit 330 may be configured based on indications received bydiagnostic unit 310. In some embodiments, diagnostic unit 310 mayautomatically provide therapy unit 330 an indication of the appropriatetherapeutic auditory stimulation. As an additional example, diagnosticunit 310 may provide values that therapy unit 330 uses to generatetherapeutic auditory stimulation. In other embodiments, a user mayconfigure therapy unit 330 based on indications provided by diagnosticunit 310. As described below with reference to FIG. 5, therapy unit 330may comprise means for generating the stimulation signal. Additionallyor alternatively, therapy unit 330 may comprise means for providingtherapeutic auditory stimulation to one or more patients.

Therapy unit 330 may comprise one or more devices communicativelyconnected to diagnostic unit 310, consistent with disclosed embodiments.For example, diagnostic unit 310 may transmit and/or receive informationover a computer network connection or a telephonic connection withtherapy unit 330. A computer network connection may include one or morewireless links. A telephonic connection may include one or more cellularlinks. Additionally or alternatively, a user may configure therapy unit330 using data or indications provided by diagnostic unit 310.

FIG. 4 depicts a block diagram illustrating an exemplary diagnostic unitfor receiving indications of the condition of a patient, consistent withdisclosed embodiments. In some embodiments, diagnostic unit 310 maycomprise one or more electronics devices. For example, diagnostic unit310 may comprise a signal conditioning and registration device 400,electrodes (such as electrodes 412 and 414), and heart rate monitor 418.In some embodiments, signal conditioning and registration device 400 maybe a single device, such as an EEG machine. In certain embodimentssignal conditioning and registration device 400 may comprise multipledevices, such as a data acquisition unit and a general-purpose computerconfigured to process data received from the data acquisition unit.

Signal conditioning unit 410 may comprise electronic componentsconsistent with disclosed embodiments. In some embodiments, signalconditioning unit 410 may comprise one or more connectors forelectrodes. Signal conditioning unit may comprise one or more connectorsfor signal processing unit 420. In certain embodiments, signalconditioning unit 410 may comprise active components, passivecomponents, and electromechanical components. For example, signalconditioning unit 420 may comprise amplifiers, filters, connectors,analog-to-digital connectors, digital-to-analog connectors,microcontrollers, processors, and/or memories.

Signal conditioning unit 410 may receive one or more EEG signals fromone or more electrodes consistent with disclosed embodiments. In someembodiments, signal conditioning unit 410 may condition the one or moreelectrical signals in preparation for, or as part of data acquisition,consistent with disclosed embodiments. In some embodiments, the EEGelectrical signals may correspond to measurements of electrodepotential. For example, EEGs signals may correspond to differentialmeasurements of electrode potential between multiple electrodes. In someembodiments, the one or more electrodes may include a referenceelectrode. A differential measurement may depend on the differencebetween the electrical potential of the reference electrode and theelectrode potential of another electrode. In some embodiments, thereference electrode may be connected to ground. In certain embodiments,the EEG signals may correspond to single-ended or pseudo-differentialmeasurements of electrode potentials.

Signal conditioning unit 410 may receive a heart rate signal from aheart rate monitor 418 consistent with disclosed embodiments. In someembodiments, heart rate monitor 418 may comprise one or more electrodesand may provide an ECG signal. In certain embodiments, heart ratemonitor 418 may comprise a pulse oximetry unit and may provide a bloodoxygenation signal.

Signal conditioning unit 410 may modify the received signals (the EGGsignals and the heart rate signal) consistent with disclosedembodiments. In some embodiments, signal conditioning unit 410 mayprovide the received signals in a suitable format for signal processingunit 420. For example, signal conditioning unit 410 may amplify thereceived signals. As an additional example, signal conditioning unit 410may digitize the received signals. Signal conditioning unit 410 maydetermine a heart rate series from the heart rate signal. In someembodiments, signal conditioning unit 410 may provide the receivedsignals to signal processing unit 420 wirelessly, such as over a Wi-Finetwork, using Bluetooth, or other methods of wireless data transmissionknown to one of skill in the art. Signal conditioning unit 410 mayprovide the signals over a network, such as a computer network.

Signal conditioning unit 410 may filter one or more of the receivedsignals consistent with disclosed embodiments. For example, filterparameters may be chosen to reject high frequency noise while preservingrelevant EEG signals. As an additional example, filter parameters may bechosen to reject low frequency noise while preserving relevant EEGsignals. In some embodiments, the bandwidth of the filtered EEG signalsprovided by the signal conditioning unit 410 may be 0.1 Hz to 100 Hz.Similarly, filter parameters may be chosen to reject high frequencynoise while preserving relevant heart rate signals. As an additionalexample, filter parameters may be chosen to reject low frequency noisewhile preserving relevant heart rate signals. Filtering may beaccomplished in hardware or software.

Signal conditioning unit 410 may electrically isolate the patient fromthe signal processing unit 420 consistent with disclosed embodiments.For example, signal conditioning unit 410 may magnetically, optically,or capacitively isolate the patient from the signal processing unit 420.In some embodiments, such isolation may be for the protection of thepatient. In certain embodiments, such isolation may be for theprotection of the Signal Processing Unit 420.

This description of signal conditioning unit 410 is intended toillustrate a potential embodiment of the disclosed systems and methodsand is not intended to be limiting. One of skill in the art wouldrecognize that other configurations and arrangements are possible.

Signal processing unit 420 may comprise electronic components consistentwith disclosed embodiments. Signal processing unit 420 may comprise amemory, a processor, and a bus. Signal processing unit 420 may comprisean input/output unit and a display. Signal processing unit 420 may beconnected to a computer network. As a non-limiting example, signalprocessing unit 420 may be a computer connected to signal conditioningunit 410 by a universal serial bus cable.

Signal processing unit may receive conditioned signals from signalconditioning unit 410 consistent with disclosed embodiments. In someembodiments, signal processing unit 410 may receive analog signals.Signal processing unit 420 may digitize analog signals received fromsignal conditioning unit 410. In some embodiments, signal processingunit 420 may receive digital signals from signal conditioning unit 410.Signal processing unit 420 may transmit and/or receive data from signalconditioning unit 410 through a wired connection or a wirelessconnection. Signal processing unit 420 may transmit and/or receive datafrom signal conditioning unit 410 over a network. In some embodiments,the input/output unit may comprise one or more connectors for connectingto signal conditioning unit 410.

Signal processing unit 420 may filter signals received from signalconditioning consistent with disclosed embodiments. For example, signalprocessing unit 420 may filter received EEG signals using analog ordigital filters. Filter parameters may be chosen to reject noise whilepreserving EEG signals according to well-known filter design methodsreadily known to one of skill in the art. In some embodiments, thebandwidth of the filtered EEG signals may be 0.1 Hz to 100 Hz. As anadditional example, signal processing unit 420 may filter a heart ratesignal received from the signal conditioning unit. Filtering may beaccomplished in hardware or software.

Signal processing unit 420 may amplify signals received from signalconditioning unit 410 consistent with disclosed embodiments. Signalprocessing unit 420 may acquire analog signals consistent with disclosedembodiments. Signal processing unit 420 may amplify received signals forpurposes of convenient analysis, for example by normalizing signals.

Signal processing unit 420 may transform signals received from signalconditioning unit 410 consistent with disclosed embodiments. Forexample, signal processing unit 420 may compute a power spectral densityof one or more of the received EEG signals. Signal processing unit 420may determine a total signal power from the power spectral density.Signal processing unit 420 may determine signal powers for EEG bandsfrom the power spectral density. Signal processing unit 420 maydetermine the contribution of one or more EEG signal bands to the totalpower for the signal. For example, signal processing unit 420 maydetermine the fraction of the total signal power contributed by thecomponents of the EEG signal in the delta wave EEG band. The relativecontributions of the EEG signals may indicate a mental state of thepatient. For example, excessive contributions from lower-frequency EEGbands may indicate a depressive disorder. Conversely, excessivecontributions from higher-frequency EEG bands may indicate an anxietydisorder.

Signal processing unit 420 may also determine a heart rate series fromthe heart rate signal consistent with disclosed embodiments. Signalprocessing unit 420 may receive a heart rate series from the signalconditioning unit 410. Signal processing unit 420 may transform theheart rate series into a power spectral density. In some embodiments,this transformation may use parametric methods such a fast Fouriertransform, non-parametric methods such as autoregressive models, orother methods known to those of skill in the art. In some embodiments,the power spectral density may comprise components at varyingfrequencies. For example, the power spectral density may comprise a lowfrequency component associated with fluctuations sympathetic nerveactivity. In some embodiments this low frequency component may becentered on a frequency in the range of 0.04-0.15 Hz. As anotherexample, in some embodiments the power spectral density may comprise ahigh frequency component associated with fluctuations of vagal-cardiacnerve activity. In some embodiments this high frequency component may becentered on a frequency in the range of 0.15-40 Hz. Signal processingunit 420 may determine a ratio of the low frequency components to thehigh frequency components of the power spectrum. This ratio may indicatethe balance between the contributions of the sympathetic andparasympathetic components of the autonomic nervous system to the heartrate. For example, a reduced ratio or decreased contribution fromhigh-frequency components may indicate a depressive or an anxietydisorder. Other measures known to one of skill in the art, such as thestandard deviation the heart rate period, may also provide indicationsof the mental state of the patient. Thus the disclosed embodiments arenot intended to be limiting.

Signal processing unit 420 may display information consistent withdisclosed embodiments. For example, signal processing unit 420 maydisplay information corresponding to one or more received signals. Insome embodiments, signal processing unit 420 may display frequencydomain information for a received EEG signal. For example, signalprocessing unit 420 may display the normalized contribution to the totalEEG signal power from one or more EEG bands. In certain embodiments,signal processing unit 420 may display heart rate information. Forexample, signal processing unit 420 may display statistics related toheart rate variability. In some embodiments, signal processing unit 420may display the ratio of the low frequency components of the heart ratepower spectrum to the high frequency components of the heart rate powerspectrum.

This description of signal processing unit 420 is intended to illustratea potential embodiment of the disclosed systems and methods and is notintended to be limiting. One of skill in the art would recognize thatother configurations and arrangements are possible.

The signal conditioning unit 410 may be connected to electrodes forrecording electrical activity on the scalp. This electrical activity mayresult from the activity of the brain of a patient. Many configurationsof electrodes, differing in number and placement, are suitable for usewith the disclosed systems and methods. Standardized electrodeplacements include the 10-20 system, which includes 21 electrodes, andthe extended 10-20 system, or 10% system, which includes 74 electrodes.Consistent with the disclosed systems and embodiments, electrodes may beplaced at some or all of the locations described in these standards. Forexample, consistent with disclosed embodiments, frontal electrodes 412may be placed bilaterally over the frontal lobes of the patient andoccipital electrodes 414 may be placed bilaterally over the occipitallobes of the patient. In some embodiments, a reference electrode may beplaced on, behind, or near an car of the patient. In certainembodiments, this reference electrode may be connected to ground. Aswould be recognized by one of skill in the art, alternative electrodeplacement locations may be used. The described electrode position is notintended to be limiting.

Electrodes, such as occipital electrodes 414, may be disc electrodes,cup electrode, needle electrodes, or other suitable electrode typesknown to one of skill in the art. In some embodiments electrodes may beattached to the patient. For example, electrodes may be attached usingcollodion or other adhesives. In certain embodiments, headbands, straps,or caps may hold one or more electrodes in place. In certainembodiments, conductive jelly or conductive paste may be placed betweenthe electrodes and the patient to reduce the impedance of theelectrode-patient interface. In certain embodiments, dry electrodes orcapacitive electrodes may be used. Active electrodes or passiveelectrodes may be used, consistent with disclosed embodiments.

This description of diagnostic unit 400 is intended to illustratepotential embodiments of the disclosed systems and methods. Thisdescription is not intended to limit the disclosed systems and methodsto any particular device or arrangement of devices. One of skill in theart would recognize other possible configurations and arrangementsconsistent with disclosed embodiments. For example, electrodes, signalconditioning unit 410 and signal processing unit 420 may each comprisemultiple devices that together perform the disclosed functions.Conversely, a single device may perform the functions of the electrodes,signal conditioning unit 410, and signal processing unit 420.

The envisioned systems and methods may use quantitative EEG fordiagnosis and patient monitoring. For example, quantitative EEG may beused to generate neuroimages showing regions of abnormal neural activityin the brain of a patient. This quantitative EEG may be obtained usingdevices and methods known to one of skill in the art. In certainaspects, diagnostic unit 310 may comprise a quantitative EEG system.

In some embodiments, the envisioned systems and methods may uselow-resolution brain electromagnetic tomography (LORETA) for diagnosisand patient monitoring. As would be recognized by one of skill in theart, LORETA may be used to diagnose abnormal mental states, such asdepression, anxiety disorders, and ADHD. In certain aspects, diagnosticunit 310 may comprise a LORETA system.

Consistent with disclosed embodiments, a quantitative EEG system orLORETA system may be configured to record multichannel EEG data. Incertain aspects, the system may use electrodes, such as electrode 430,for recording the EEG data. In some aspects, as shown in FIG. 4B, suchelectrodes may contact the head of the patient in a particular pattern.For example, nineteen channels of EEG data may be collected fromnineteen electrodes arranged on the head of the patient, each measuredwith respect to a reference electrode. As shown in FIG. 4C, quantitativeEEG systems, LORETA systems, and similar systems known to one of skillin the art may use such multichannel EEG recordings to determine neuralactivity levels. For example, such systems may be configured to identifyregions, such as region 440, in which neural activity levels areabnormally high or abnormally low. In some aspects, this identificationmay rely on the determined neural activity levels. In certain aspects,this identification may rely on a comparison between the determinedneural activity levels and historical data. This historical data may bespecific to a patient, or may reflect historical data for a populationof patients. In some embodiments, the historical data and the determinedneural activity levels may be used to calculate a statistic, such as a Zstatistic or similar statistical measure, for identifying regions ofabnormal neural activity. As would be recognized by one of skill in theart, the preceding description is not intended to be limiting.

As described above with reference to FIG. 3, in some embodiments thedisclosed methods and systems may be implemented using therapy unit 330.FIG. 5 depicts a block diagram illustrating exemplary functionalcomponents of therapy unit 330, consistent with disclosed embodiments.In some embodiments, therapy unit 330 may comprise means for generatingand means for providing therapeutic auditory stimulation. Means forgenerating the signal 510 may include one or more electronics devices.For example, generating means 510 may include a computer, such as asmartphone, tablet, laptop, desktop, or mainframe. As previouslydescribed with reference to FIG. 1, such a computer may comprise aprocessor and a non-transitory memory, such as a hard disk drive, solidstate memory, on-board cache, or other memory. In some embodiments, thecomputer may receive instructions for generating the stimulation signalthrough an input/output interface or a network interface. For example,the computer may receive a computer program that configures the computerto generate the signal. Additionally or alternatively, the computer mayreceive parameters used by a computer program to configure the computerto generate the signal. The received parameters may comprise values orindications of values. For example, the computer may receive anindication that a user has interacted with a graphical user interface toselect or configure certain therapeutic auditory stimulation. In someembodiments, generating means 510 may be incorporated into a medicalproduct, such as a special-purpose diagnostic and therapeutic productintended to treat patients using the disclosed systems and methods.

Consistent with disclosed embodiments, the means for providing thesignal 520 may obtain the stimulation signal from the generating means510 and transduce the stimulation signal into therapeutic auditorystimulation. In some embodiments, the generation means and the providingmeans may together comprise a single device. In certain embodiments, afirst device comprising the means for generating the stimulation signalmay be distinct from a second device comprising the means for providingthe therapeutic auditory stimulation. For example, the first device maybe communicatively connected to the second device.

Providing means 520 may comprise local means for providing therapeuticauditory stimulation. Additionally or alternatively, the providing meansmay include remote means for providing the therapeutic auditorystimulation. In some embodiments remote providing means may includemeans for storing the stimulation signal. In certain embodiments, remoteproviding means may include means for transmitting the stimulationsignal. Providing means 520 may include means for auditory therapy thatconverts the stimulation signal into therapeutic auditory stimulation.

Local providing means may include the contemporaneous and co-locatedgeneration and provision of the stimulation signal consistent withdisclosed embodiments. Contemporaneous generation of the stimulationsignal may include providing the signal as it is generated or providedthe stimulation signal once generation of the signal is complete.Co-located stimulus signal generation may include generating the signaland providing the signal using the same device. For example, anelectronics device, such as a music player, a computer, or a smartphonemay both generate the stimulation signal and provide the stimulationsignal for therapeutic auditory stimulation. As an additional example, amedical product, such as a special purpose therapeutic device, maygenerate and provide the stimulation signal.

Remote provide means may use means for storing the stimulation signaland means for transmitting the stimulation signal to enable a temporalor spatial separation between the generation of the stimulation signaland the provision of the therapeutic auditory stimulation. As anon-limiting example, the stimulation signal may be stored on anon-transitory computer-readable medium, such as the non-transitorymemory described above. For example the signal may be stored on acompact disc, DVD, magnetic tape, disk drive, or flash memory, orsimilar storage medium. An analog signal or a digital signal may bestored. A digital signal may be stored as an audio file in any of anumber of compressed or uncompressed file formats known to one of skillin the art.

In some embodiments, the signal may be stored as a sequence of values.These values may represent the amplitude of the signal. These values maybe implicitly or explicitly associated with times. The values maycorrespond to or be derived from the amplitude of the signal as sampledat various points of time. In certain embodiments, the memory may storeinstructions for generating the signal. For example, the instructionsmay indicate a choice between pre-existing signals. Such pre-existingsignals may be preprogrammed. As another example, the storedinstructions may be parameters for use in generating the signal. Forexample, the parameters may be frequencies, durations, delays,amplitudes, rise or fall times, or other characteristics of signalsconsistent with disclosed embodiments.

Transmission means may permit the spatial separation of generation ofthe signal and the therapeutic use of the signal. In certainembodiments, the signal may be generated and then transmitted fortherapeutic use. In some embodiments, the signal may be transmitted asthe signal is being generated. Consistent with disclosed embodiments,the signal may be transmitted over a network, such as a cellular phonenetwork, the public switched telephone network, or a computer network.The signal may also be transmitted stored in a computer-readable medium,such as a compact disc, DVD, flash memory, or audiotape. For example, anaudio file containing the stimulation signal may be downloaded orstreamed over a computer network from a server to a music player. Asanother example, the stimulation signal may be received at a telephoneduring a telephone call. As an additional example, the stimulationsignal may be received as an attachment to message or email sent to acomputer or a phone, such as a smartphone.

Audio therapy means may convert the stimulation signal into therapeuticauditory stimulation using any transduction method known to one of skillin the art. For example, audio therapy means may comprise audio speakersthat convert a stimulation signal into therapeutic auditory stimulation.Consistent with disclosed embodiments, such audio speakers may beincorporated into electronics devices. For example, electronics devicesmay include consumer electronics capable of playing music, such as musicplayers, computers, or telephones. Electronics devices may includemedical devices, such as special-purpose diagnostic and therapeuticdevices intended to treat patients using the disclosed systems andmethods. The audio therapy means may be configured to produce audibletherapeutic auditory stimulation with amplitude less than 50 decibels.Preferably, the amplitude of therapeutic auditory stimulation may rangebetween 20-40 decibels.

Consistent with disclosed embodiments, therapeutic auditory stimulationmay be provided repeatedly according to a stimulation regime. Thestimulation regime may prescribe an initial treatment phase and abooster phase. Each phase may comprise stimulation sessions providedover a time period of multiple weeks. Stimulation sessions may beprovided more frequently in the initial treatment phase than in thebooster phase. Preferably, stimulation sessions may be provided everyother day. More preferably, stimulation sessions may be provided 5 timesduring a two week block. During the booster phase, sessions oftherapeutic auditory stimulation may be separated by multiple weeks.

In some embodiments, the initial treatment phase may be divided intoblocks, separated by assessment intervals. During each block,stimulation sessions may be provided. During assessment intervals theeffects of stimulation may be assessed. As described above, assessmentmay comprise the administration of diagnostic questionnaires orinterviews.

In some embodiments, parameters of therapeutic auditory stimulation maybe held constant between sessions. In certain embodiments, therapeuticauditory stimulation parameters may vary between sessions based on theeffectiveness of the current stimulation parameters.

FIG. 6A depicts an exemplary method for providing therapeutic auditorystimulation, consistent with disclosed embodiments. One of skill in theart would recognize that the particular order and sequence of events maybe altered and is not intended to be limiting. Furthermore, steps may beremoved or added without departing from the envisioned embodiments. Forexample, the sequence of steps depicted in FIG. 6 may be preferable forinitially determining effective therapeutic auditory stimulation.Consistent with disclosed embodiments, subsequent stimulation sessionsinclude only a subset of the steps shown in FIG. 6A, such as one or moreinstances of providing auditory stimulation.

Consistent with disclosed embodiments diagnostic unit 310 may be used toregister the electroencephalogram of a patient (step 610). The processof registering the electroencephalogram of a patient is well known inthe art and is included for completeness of description. In someembodiments, registering the EEG may involve multiple trials. Inaspects, one or more trials may be conducted to establish a baselineEEG. For example, a first trial may be conducted with the patient's eyesopen. A second trial may be conducted with the patient's eyes closed. Incertain aspects, these trials may last one minute.

While these trials are conducted, the diagnostic unit may record EEGdata and values extracted from the EEG data. For example, with referenceto FIG. 4 discussed above, the diagnostic unit may store the datareceived by the signal processing unit 420. As an additionalnon-limiting example, signal processing unit 420 may store the resultsof transforming the received data, such as the signal powers for EEGbands, or the contribution of one or more EEG signal bands to the totalpower for the signal. As a further example, the diagnostic unit maystore heart rate data received by the signal processing unit 420. As anon-limiting example, diagnostic unit 310 may store transformed heartrate data, such as the ratio of the low frequency components to the highfrequency components of the power spectrum.

In some embodiments, diagnostics unit 310 may display, or provide fordisplay, some or all of the stored data. A healthcare practitioner mayuse diagnostic unit 310 to assess the electroencephalogram of thepatient. The healthcare practitioner may be, without limitation, adoctor, nurse, physician's assistant, therapist, psychologist, or otherindividual that provides patient care. In other embodiments, diagnosticunit 310 may be configured to automatically determine appropriatetherapeutic auditory stimulation. In further embodiments, the patientmay interact with diagnostic unit 310 to determine appropriate auditorystimulation.

FIG. 6B depicts an exemplary illustration of a user interface 650 forproviding therapeutic auditory stimulation. User interface 650 mayinclude EEG graphs 660 corresponding to each of frontal electrodes 412and occipital electrodes 414. EEG Graphs 660 may display thecontribution of one or more EEG bands to the overall signal powermeasured at each of the electrodes. Heart rate graph 670 may display theaverage heart rate of the patient during the trial. Heart ratevariability graph 680 may show the relative contributions of the low andhigh frequency components of the heart rate to the overall signal powerof the heat rate. Previously stored trials may be accessed throughstored trial menu 690. Individual stimulation waveforms may be selectedthrough stimulation waveform menu 695. As would be recognized by one ofskill in the art, user interface 650 may be configured such thatsimulation waveforms may be provided by interacting with stimulationwaveform menu 695, or another component of user interface 650.

Consistent with disclosed embodiments, appropriate therapeutic auditorystimulation may be determined in step 620. In certain aspects, thisdetermination may be based on the results provided by diagnostic unit310. In some embodiments, the determination may be based on theidentification of abnormal EEG results, such as EEG results deviatingfrom the typical or expected results for the patient, based on one ormore of the age, present condition, and medical history of the patent.In some instances, the patient may exhibit an elevated contribution tototal EEG signal power from one or more EEG bands. For example, thepatient may exhibit minimal or abnormally low contributions of a firstEEG band. This low contribution may imply an excessive contribution fromanother EEG band.

The determination of appropriate therapeutic auditory stimulation instep 620 may additionally or alternatively depend on other diagnosticcriteria. In some embodiments, step 610 may comprise receiving theresults of a diagnostic test. In certain aspects, this diagnostic testmay involve an anatomical or physiological parameter of the patient. Asa non-limiting example, the diagnostic test may comprise clinicallaboratory test, such as a test performed in an anatomic pathologylaboratory or a clinical pathology laboratory. In some embodiments, ahealthcare practitioner may evaluate the patient using a questionnaireor assessment. In certain aspects, this questionnaire or assessment maybe global, such as Clinical Global Impression-Severity and Improvement,Comprehensive Psychopathological Rating Scale, Global Assessment ofFunctioning, Children's Global Assessment Scale, or similar rating scaleand/or assessment.

Additionally or alternatively, a healthcare practitioner may evaluatethe patient using a questionnaire or assessment specific to a mental orpsychological disorder. As a non-limiting example, a healthcarepractitioner may evaluate the ADHD status of the patient using the AdultADHD Self-Report Scale, Brown Attention Deficit Disorder Scales,Swanson, Nolan and Pelham Teacher and Parent Rating Scale, VanderbiltADHD Diagnostic Rating Scale, ADHD Rating Scale, or similar ratingscales and/or assessments. As a further non-limiting example, ahealthcare practitioner may evaluate the Autism spectrum status of thepatient using the Adult Asperger Assessment, Australian scale forAsperger's syndrome, Autism Spectrum Quotient, Childhood Autism RatingScale, Childhood Autism Spectrum Test, Q-CHAT, Autism DiagnosticObservation Schedule, or similar rating scales and/or assessments. As anadditional non-limiting example, a healthcare practitioner may evaluatethe patient for anxiety disorders using the Pediatric Anxiety RatingScale, Child Anxiety Impact Scale, the Screen for Child Anxiety RelatedEmotional Disorders, the Brief Family Assessment Measure-III, and theSleep Disturbance Scale, Beck Anxiety Inventory, Clinician AdministeredPTSD Scale, Daily Assessment of Symptoms—Anxiety, Generalized AnxietyDisorder 7, Hamilton Anxiety Scale, Hospital Anxiety and DepressionScale, Panic and Agoraphobia Scale, Panic Disorder Severity Scale, PTSDSymptom Scale-Self-Report Version, Social Phobia Inventory, TraumaScreening Questionnaire. Yale-Brown Obsessive Compulsive Scale, ZungSelf-Rating Anxiety Scale, or similar rating scales and/or assessments.As an additional non-limiting example, a healthcare practitioner mayevaluate the patient for dementia using the Abbreviated mental testscore, Clinical Dementia Rating, General Practitioner Assessment OfCognition, Informant Questionnaire on Cognitive Decline in the Elderly,Mini-mental state examination, or similar rating scales and/orassessments. As an additional non-limiting example, a healthcarepractitioner may evaluate the patient for depression using the BeckDepression Inventory, Beck Hopelessness Scale, Centre forEpidemiological Studies—Depression Scale, Edinburgh Postnatal DepressionScale, Geriatric Depression Scale, Hamilton Rating Scale for Depression,Hospital Anxiety and Depression Scale, Kutcher Adolescent DepressionScale, Major Depression Inventory, Montgomery-Asberg Depression RatingScale, Zung Self-Rating Depression Scale, or similar rating scalesand/or assessments. As an additional non-limiting example, a healthcarepractitioner may evaluate the patient for other psychological disordersusing the Altman Self-Rating Mania Scale, Young Mania Rating Scale,Buss-Perry Aggression Questionnaire, Hare Psychopathy Checklist,Minnesota Multiphasic Personality Inventory or similar rating scalesand/or assessments.

As would be recognized by one of skill in the art, a healthcarepractitioner may evaluate the patient additionally or alternativelyusing guided or semi-structured interviews, such as the AnxietyDisorders Interview Schedule for DSM-IV, Research and Lifetime Versionfor Children and Parents. Self-reporting may also be used to gauge theincidence and severity of adverse behaviors, such as self-harm, or theoccurrence of general health problems.

As an additional example, a healthcare practitioner may evaluate thepatient using a questionnaire or assessment specific to an anatomical orphysiological disorder. For example, a healthcare practitioner mayevaluate the patient for Parkinson's using one or more of theInternational Parkinson and Movement Disorder Society diagnosticquestionnaires, as would be understood by one of skill in the art.Additionally, consistent with disclosed embodiments, such questionnairesmay be used in the diagnosis of headache and migraine, constipation,diabetes, cerebral palsy, stuttering, psychosomatic disorders, and paindisorders, as would be understood by one of skill in the art.

In some embodiments, the determination of appropriate therapeuticauditory stimulation in step 620 may depend on diagnostic testsconducted as part of a therapeutic auditory stimulation session. Forexample, the diagnostic test may be conduct during a therapeuticauditory stimulation session prior to provision of the therapeuticauditory stimulation. In certain embodiments, appropriate therapeuticauditory stimulation may be determined based on results of one or morepreviously conducted diagnostic test. In certain aspects, diagnosticunit 310 may be configured to determine appropriate therapeutic auditorystimulation based on the results of the diagnostic test. In someaspects, a healthcare practitioner may determine appropriate therapeuticauditory stimulation based on the results of the diagnostic test. Insome aspects, the healthcare practitioner may interact with diagnosticunit 310 to determine appropriate therapeutic auditory stimulation basedon the results of the diagnostic test.

As described in greater detail with reference to FIG. 7A-7D below,therapeutic auditory stimulation may comprise one or more stimulationwaveforms. In certain aspects, the one or more stimulation waveforms maycorrespond to the excessively contributing EEG band. In certaininstances, each of the EEG bands may contribute equally to the EEG powersignal. In certain aspects, the appropriate therapeutic auditorystimulation may include one or more stimulation waveforms correspondingto a midrange EEG band. Consistent with disclosed embodiment, an EEGband defined with reference to a first EGG frequency and a second EEGfrequency may correspond to a stimulation waveform having a firstfrequency associated with the first EEG frequency and a second frequencyassociated with the second EEG frequency. For example, the first EEGfrequency may equal the first stimulation waveform frequency. As anotherexample, the second EEG frequency may equal the second stimulationwaveform frequency.

In some embodiments, the therapeutic auditory stimulation may comprise atrain of stimulation waveforms. In certain aspects, the firststimulation waveform in the train may correspond to the excessivelycontributing EEG band. In various aspects, the first stimulationwaveform may correspond to a chosen midrange EEG band. In someembodiments, subsequent stimulation waveforms in the train maycorrespond to progressively higher frequency EEG bands. In otherembodiments, subsequent waveforms may correspond to progressively lowerfrequency EEG bands. For example, one or more stimulation waveforms maycorrespond to the theta EEG band. These stimulation waveforms maycomprise a modulating waveform corresponding to the Theta EEG band. Inone aspect, the modulating waveform may have a frequency that changesbetween 4 Hz and 7 Hz, in accordance with frequency boundaries of thetheta EEG band.

In various embodiments, determination of the stimulation waveform mayadditionally or alternatively consider the heart rate and the heart ratevariability of the patient. For example, the appropriate therapeuticstimulation may depend on the relative values of the low frequencycomponent of the heart rate variability and the high frequency componentof the heart rate variability. In some aspects, the appropriatetherapeutic stimulation may include an initial stimulation waveformcorresponding to a low EEG band when the low frequency component of theheart rate is less than the high frequency component of the heart rate.In various aspects the appropriate therapeutic stimulation may includean initial stimulation waveform corresponding to a high EEG band whenthe low frequency component of the heart rate is greater than the highfrequency component of the heart rate.

As described with reference to step 610, in various embodiments thehealthcare practitioner, diagnostic unit 310, or patient may determinethe appropriate therapeutic auditory stimulation. In some embodiments,this determination may be made with reference to the displayed resultsof diagnostic unit 310.

TABLE 1 Stimulation Signals for Different Combinations of EEG FrequencyBand Contributions and Heart Rate Variability (Eyes Closed). Table 1depicts a non-limiting example of the stimulation waveforms comprisingthe appropriate therapeutic auditory stimulation for differentcombinations of results provided by diagnostic unit 310. The first fourcolumns indicate the percentage of the total spectral densityrespectively contributed by the theta, alpha, beta 1, and beta 2 EEGfrequency bands. The fifth column indicates the relative contribution ofthe high and low frequency components of the heart rate variability. Thesixth column indicates an appropriate corresponding stimulation signalfor therapeutic auditory stimulation comprising a sequence ofstimulation waveforms. The values in this table are for measurementsconducted with the patient's eyes closed. The correspondence defined bythis table may be acceptable for many of the conditions described above.For example, this correspon- dence may be used when treating depression,anxiety, pain, dementia, and autism spectrum disorders. As would beunderstood by one of skill in the art, this table non-limiting andprovided for illustrative purposes. % % % % SVB theta alpha beta 1 beta2 ratio Stimulation Signal >20 <60 <10 <10 LF < HF Delta, Theta,Alpha >10 >60 <20 <10 LF <= HF Theta, Alpha, Beta 1 <20 <60 >10 >10LF >= HF Alpha, Beta 1, Beta 2 <10 >20 <60 >10 LF > HF Beta 1 , Beta 2,Gamma

Consistent with disclosed embodiments, therapeutic unit 330 may beconfigured to provide the appropriate therapeutic stimulation in step630. In some embodiments, therapeutic unit 330 may be configuredautomatically by diagnostic unit 310. In various embodiments,therapeutic unit 330 may be configured by the healthcare practitioner.In certain embodiments, therapeutic unit 330 may be configured by thepatient.

In some aspects, configuring therapeutic unit 330 may comprise selectingone or more stimulation waveforms. In some instances stimulationwaveforms may be selected by interacting with a graphical userinterface. In some embodiments, therapeutic unit 330 may be usedrepeatedly following selection of a stimulation regime. In otherembodiments, therapeutic unit 330 may require selection of eachstimulation waveform comprising the therapeutic auditory stimulation.For example, the patient or healthcare practitioner may need to selectthe next stimulation waveform once the current stimulation waveform hascompleted. In certain aspects, configuring therapeutic unit 330 maycomprise providing parameters defining the stimulation waveform. Suchparameters may define, as a non-limiting example, the amplitude ofauditory stimulation, the number of stimulation waveforms provided, theEEG band corresponding to each stimulation waveform, frequencies of thestimulation waveform, durations of the stimulation waveform, and thenature of any components of the stimulation wave (as a non-limitingexample, the numbering, ordering, and duration of components of thestimulation waveform).

As described in greater detail below, with respect to FIGS. 7A-71), theduration of therapeutic auditory stimulation may vary. In someembodiments, this duration may depend on the number of stimulationwaveforms comprising the therapeutic auditory stimulation. In otherembodiments, the duration of the therapeutic auditory stimulation maydepend on the duration of the stimulation waveforms. Preferably, theduration of the stimulation waveforms may be between 180 and 300seconds. Preferably, the duration of the therapeutic auditorystimulation may be between 15 and 25 minutes. However, one of ordinaryskill in the art would recognize that shorter or longer durations arepossible for both the stimulation waveforms and the therapeutic auditorystimulation.

As described with respect to FIG. 5, therapy unit 330 may comprise meansfor generating stimulation signals and means for providing stimulationsignals. The means for providing stimulation signal may include localmeans for providing stimulation signals. The means for providingstimulation signals may include remote means for providing stimulationsignals. Remote means for providing stimulation signals may includetransmission means or storage means for spatially and/or temporallyseparating the generation of the stimulation signals from the provisionof the therapeutic auditory stimulation. According to the envisionedmethods and systems, the structures and functions of diagnostic unit 310and therapeutic unit 330 may be distributed among one or more devices.

Consistent with disclosed embodiments, diagnostic unit 310 may be usedto re-assess the electroencephalogram of the patient following provisionof therapeutic auditory stimulation. In some embodiments, thisreassessment may comprise re-registering the EEG. The EEG may beregistered with the patient's eyes open. Additionally, the EEG may bere-registered with the patients eyes closed. The diagnostic device 310may store the EEG waveforms recorded during re-registration. Thediagnostic device may display, or provide for display, the signalsreceived by signal processing 420. The diagnostic device may display, orprovide for display, the signals generated by signal processing 420.Based on the results of the re-registration, the therapeutic stimulationregime may be selected. In some embodiments, the healthcare practitionermay select the stimulation regime. In certain embodiments, thediagnostic unit 310 may select the stimulation regime. In variousembodiments, the patient may select the stimulation regime.

In some embodiments, once the stimulation regime is selected, thepatient may be enabled to provide themselves therapeutic auditorystimulation. In certain aspects, the patient may be provided acomputer-readable medium storing the therapeutic auditory stimulation.In various aspects, the patent may be provided a device that generatesand provides the therapeutic auditory stimulation. In some aspects, thepatient may be granted access to a device that generates the therapeuticauditory stimulation. For example, the patient may be enabled to contacta device over a network, such as a telephone or computer network andreceive the therapeutic auditory stimulation from the device over thenetwork. As an additional example, the patient may listen to thetherapeutic auditory stimulation over a telephone connection. In someembodiments, the patient may visit a healthcare practitioner to receivethe therapeutic auditory stimulation.

FIGS. 7A-7D illustrate characteristics of exemplary waveforms fortherapeutic auditory stimulation, consistent with disclosed embodiments.As discussed above with respect to FIG. 3 and FIG. 5, therapy unit 330may comprise means for generating the stimulation signal. Therapy unit330 may also comprise means for providing the signal and converting thestimulation signal into therapeutic auditory stimulation.

As shown in FIG. 7A, stimulation signal 700 may comprise one or morestimulation waveforms consistent with disclosed embodiments. In someembodiments, first waveform 702, second waveform 704, and third waveform706 may comprise a train of waveforms. In certain embodiments, aninterval of time may separate one or more adjacent stimulationwaveforms, such as first stimulation waveform 702 and second waveform704. For example, first stimulation waveform 702 may first be selectedand provided and then second stimulation waveform 704 may next beselected and provided. In other embodiments, no interval of time mayseparate adjacent stimulation waveforms. In some embodiments, thewaveforms may differ in at least one or more of amplitude, duration, orfrequency. The disclosed embodiments are not limited to stimulationsignals comprising three waveforms: one of skill in the art wouldrecognize that a lesser or a greater number of stimulation waveforms maybe included in stimulation signal 700.

Consistent with disclosed embodiments, stimulation waveforms maycorrespond to EEG bands. As described above, this correspondence may bebased on the therapeutic effect of the stimulation waveform. Forexample, providing a stimulation waveform as therapeutic auditorystimulation may cause a decrease in the power spectral densitycontribution of the corresponding EEG band of an EEG signal receivedfrom the signal conditioning unit 410. This change in the correspondingEEG band may be correlated with a subjective or objective change in themental state of the patient. For example, a stimulation waveformcomprising a modulating waveform with a frequency between 4 Hz and 7 Hzmay correspond to the theta EEG band. Providing such a stimulationwaveform as therapeutic auditory stimulation may reduce the proportionalcontribution of the theta EEG band to the power spectral density of anEEG signal received from the signal conditioning unit 410.

As described above with respect to FIG. 2A, a collection of two or moreEEG frequency bands may include a high-frequency band and alow-frequency band. In some embodiments, stimulation signal 700 mayinclude a stimulation waveform corresponding to a low-frequency bandbefore a stimulation waveform corresponding to a high-frequency band.For example, in some embodiments, stimulation signal 700 may includestimulation waveforms corresponding to progressively higher EEGfrequency bands. For example, first stimulation waveform 702 maycorrespond to the Delta EEG band, second stimulation waveform 704 maycorrespond to the Theta EEG band, and third stimulation waveform maycorrespond to a Beta EEG band. Providing stimulation waveforms ofprogressively higher amplitude may increase the proportionalcontribution of higher frequency EEG bands to the power spectral densityof the EEG signal received from signal conditioning unit 410. In certainembodiments, stimulation signal 700 may include a stimulation signalcorresponding to a high-frequency band before a stimulation signalcorresponding to a low frequency band. For example, stimulation signal700 may include stimulation waveforms corresponding to progressivelylower EEG frequency bands. As would be recognized by one of skill in theart, the exact progression of stimulation waveforms would depend on thepatient's diagnosis.

Stimulation waveforms, such as stimulation waveform 702, may compriseone or more carrier waveforms consistent with disclosed embodiments. Insome embodiments, this carrier waveform may be audible. In certainembodiments, the carrier waveform may be periodic. As a non-limitingexample, the carrier waveform may approximate a sinusoidal waveform. Invarious embodiments, the carrier waveform may have a fundamentalfrequency within the audible range. For example, the carrier waveformmay have a frequency between 100 Hz and 20 kHz. Preferably, thefundamental frequency of the carrier waveform may be between 500 Hz and5 kHz. More preferably, the frequency of the carrier waveform may beapproximately 1 kHz.

A modulating waveform may modulate the carrier waveform consistent withdisclosed embodiments. In some embodiments, the modulating waveform mayhave a non-zero frequency. In certain embodiments, this frequency mayvary non-linearly with time. For example, the modulating signal may havean instantaneous frequency that varies exponentially with time. As anadditional example, the instantaneous frequency of a stimulationwaveform (such as stimulation waveform 702) may increase and decreaseexponentially over the duration of the stimulation waveform. Forexample, the instantaneous frequency may increase to a maximum frequencyand decrease to a minimum frequency. In some embodiments maximum andminimum frequency for the EEG band corresponding to the stimulationwaveform may be the maximum and minimum instantaneous frequency of themodulating waveform. For example, the maximum instantaneous frequencyfor a stimulation waveform corresponding to a theta EEG band may be 13Hz, when 13 Hz is taken to define the maximum frequency of the theta EEGband.

As shown in FIG. 7B, stimulation waveforms, such as stimulation waveform702, may comprise pairs of frequency intervals, such as 712, 714 or 716,consistent with disclosed embodiments. In some embodiments, thesefrequency interval pairs may differ in duration. In certain embodiments,an interval of time may separate one or more adjacent frequency intervalpairs, such as frequency interval pair 712 and frequency interval pair714. In other embodiments, no interval of time may separate adjacentfrequency interval pairs. During each frequency interval pair, theinstantaneous frequency of the modulating signal may vary non-linearlybetween the maximum and minimum instantaneous frequency for thatstimulation waveform. For example, during a frequency interval pair, theinstantaneous frequency may increase exponentially from the minimumfrequency to the maximum frequency and then decease exponentially backto the minimum frequency. The number of frequency interval pairs in astimulation waveform may range from 4 to 12 pairs. Preferably, thenumber of stimulation interval pairs may range from 7 to 10 pairs.

In certain embodiments, stimulation waveforms may include only oneinterval. Over that interval, the instantaneous frequency of themodulating signal may vary non-linearly. The instantaneous frequency ofthe modulating signal may increase from the minimum to the maximuminstantaneous frequency for that stimulation waveform. The instantaneousfrequency of the modulating signal may decrease from the maximum to theminimum instantaneous frequency for that stimulation waveform.

As shown in FIG. 7C, frequency interval pairs, such as frequencyinterval pair 712, may comprise frequency intervals. In certain aspects,frequency interval pairs may comprise increasing frequency intervals(such as 722) and decreasing frequency intervals (such as 724). In someembodiments, the increasing frequency interval may precede thedecreasing frequency interval in a frequency interval pair. In certainembodiments, an interval of time may separate the increasing anddecreasing frequency intervals in one or more frequency interval pairs.In other embodiments, no interval of time separates increasing anddecreasing frequency intervals.

The instantaneous frequency of the modulating waveform may increasenon-linearly during the increasing frequency interval consistent withdisclosed embodiments. For example, the instantaneous frequency of themodulating waveform may increase exponentially from the minimumfrequency to the maximum frequency of the stimulation waveform duringthe increasing stimulation interval. In certain embodiments, theinstantaneous frequency of the modulating waveform may decreasenon-linearly during the decreasing frequency interval. For example, theinstantaneous frequency of the modulating waveform may decreaseexponentially from the maximum frequency to the minimum frequency of thestimulation waveform during the decreasing stimulation interval.

The duration of the increasing and decreasing frequency intervalscomprising a frequency interval pair in a stimulation waveform maydepend on the EEG bands, consistent with disclosed embodiments. In someembodiments, these durations may be selected based on the minimum andmaximum frequencies defining certain of the EEG bands. For example, theselected durations may equal a number of seconds corresponding to one ofthe minimum or maximum frequencies, expressed in hertz. In someinstances, the certain EEG bands may be near in frequency to the EEGband corresponding to the stimulation waveform. For example, thedurations of the increasing and decreasing frequency intervalscomprising the frequency interval pairs in a stimulation waveformcorresponding to the alpha EEG band may be chosen from the minimum andmaximum frequencies defining the alpha, delta, theta, and beta 1 EEGbands. Similarly, the durations of the increasing and decreasingfrequency intervals comprising the frequency interval pairs in astimulation waveform corresponding to the gamma EEG band may be chosenfrom the minimum and maximum frequencies defining the gamma, beta 2 andbeta 1 EEG bands.

Consistent with disclosed embodiments, the durations of increasing anddecreasing frequency intervals in a stimulation waveform may varyaccording to a pattern. In certain embodiments, the durations of theincreasing and decreasing frequency intervals may progressivelyincrease. For example, frequency interval pair 712 may compriseincreasing frequency interval 722 with duration 8 seconds and decreasingfrequency interval 724 with duration 13 seconds. In this example,frequency interval pair 714 may then comprise an increasing frequencyinterval with duration 13 seconds and a decreasing frequency intervalwith duration 21 seconds. In certain embodiments, the durations of theincreasing and decreasing frequency intervals may progressivelydecrease. For example, frequency interval pair 712 may compriseincreasing frequency interval 722 with duration 13 seconds anddecreasing frequency interval 724 with duration 21 seconds. In thisexample, frequency interval pair 714 may then comprise an increasingfrequency interval with duration 8 seconds and a decreasing frequencyinterval with duration 13 seconds. As shown in Table 2, in someembodiments, the duration of the increasing and decreasing frequencyintervals may first increase and then decrease, or first decrease andthen increase. In some embodiments, the duration of the decreasingfrequency interval in a frequency interval pair exceeds the duration ofthe increasing frequency interval in the frequency interval par.

TABLE 2 Exemplary Stimulation Waveforms. Each stimulation waveform isidentified by a corresponding EEG band (alpha → gamma). The second andthird columns show the maximum and minimum instantaneous frequencies ofthe modulating waveform for the stimulation waveform. The forth columnshows the duration in seconds of the increasing and decreasing frequencyintervals for each frequency interval pair in the stimulation waveform.The fifth column shows the total duration of the stimulus waveform inseconds. As one of skill in the art would appreciate, the exemplarystimulation waveforms depicted in Table 2 are not intended to belimiting. Corre- Maximum Minimum Total sponding Frequency FrequencyDuration of Intervals (s) Dura- EEG Band (Hz) (Hz)(increasing-decreasing) tion (s) Alpha 13 8 13-21, 8-13, 5-8, 3-5, 5-8,186 8-13, 13-21, 8-13, 5-8, 3-5 Theta 8 5 13-21, 8-13, 5-8, 3-5, 5-8,186 8-13, 13-21, 8-13, 5-8, 3-5 Delta 5 3 13-21, 8-13, 5-8, 3-5, 5-8,186 8-13, 13-21, 8-13, 5-8, 3-5 Beta 1 21 13 13-21, 8-13, 5-8, 3-5, 5-8,186 8-13, 13-21, 8-13, 5-8, 3-5 Beta 2 34 21 21-34, 13-21, 8-13, 13-21,254 21-34, 13-21, 8-13 Gamma 55 34 34-55, 21-34, 13-21, 21-34, 25434-55, 21-34, 13-21

In some embodiments, the duration of an interval may approximate be aconstant multiple of the duration of a previous interval. In someembodiments, this multiple may approximate φ. In certain aspects, theduration of a decreasing interval in an interval pair may be anapproximately constant multiple of the duration of the increasinginterval in the interval pair. Table 2 provides non-limiting examples ofstimulation waveforms with intervals meeting this duration criteria. Forexample, the stimulation waveform gamma includes a first increasinginterval with duration 34 seconds, a first decreasing interval withduration 55 seconds (a ratio of 1.617), a second increasing intervalwith duration 21 seconds, and a second decreasing interval with duration34 seconds (a ratio of 1.619), etc. In some aspects the ratio between aninterval in a first pair and the corresponding interval in a second pairmay approximate φ. As an additional example, the stimulation waveformgamma includes a first increasing interval of duration 34 second and asecond increasing interval of duration 21 seconds (a ratio of 1.619).

FIG. 7D shows a schematic of the amplitude-modulated carrier waveformconsistent with disclosed embodiments. The schematic depicts theamplitude-modulated carrier waveform during a decreasing frequencyinterval, such as decreasing frequency interval 724. The modulatingwaveform defines the envelope of the amplitude-modulated carrierwaveform, while the frequency carrier waveform is illustratedschematically at time 732 and 734. As shown at time 732 and 734, thefrequency of the modulating waveform progressively decreases, while thefrequency of the carrier waveform remains constant.

In some embodiments, the instantaneous frequency of the modulatingwaveform during an increasing frequency interval may be given as:

F _(mod) =Fmin+(Fmax−Fmin)*(1−exp(−5t/Trise))

Where F_(mod) is the instantaneous frequency, F_(min) is the minimumfrequency of the stimulation waveform, Fmax is the maximum frequency ofthe stimulation waveform, and T_(rise) is the rise time of thefrequency. In some embodiments, T_(rise) may be the duration of theincreasing frequency interval. In some embodiments, as shown above, themultiplier of t in the argument to the exponential may be −5. In certainaspects, the multiplier oft in the argument to the exponential may beselected from the range of [−7, −3]. In this manner the rapidity of thefrequency change may be modulated to further reduce the likelihood ofpatient adaptation to the therapeutic auditory stimulation.

In some embodiments, the instantaneous frequency of the modulatingwaveform during a decreasing frequency interval may be given as:

F _(mod) =Fmin+(Fmax−Fmin)*(1−exp(−5t/Trise))

Where F_(mod) is the instantaneous frequency, F_(min) is the minimumfrequency of the stimulation waveform, F_(max) is the maximum frequencyof the stimulation waveform, and T_(rise) is the rise time of thefrequency. In some embodiments, T_(rise) may be the duration of thedecreasing frequency interval. In some embodiments, as shown above, themultiplier oft in the argument to the exponential may be −5. In certainaspects, the multiplier of t in the in the argument to the exponentialmay be selected from the range of [−7, −3]. In certain aspects, themultiplier of t in the argument to the exponential may be selected fromthe range of [−7, −3]. In this manner the rapidity of the frequencychange may be modulated to further reduce the likelihood of patientadaptation to the therapeutic auditory stimulation.

One of skill in the art would recognize that alternative stimulationsignals may also be used. For example, in some embodiments, thestimulation signal may comprise multiple stimulation waveforms, eacheither increasing or decreasing in frequency. For each of thesestimulation waveforms, the instantaneous frequency of the modulatingsignal may vary non-linearly from a first instantaneous frequency forthat stimulation waveform to a second instantaneous frequency for thatstimulation waveform. For example, a stimulation signal may comprise afirst stimulation waveform corresponding to the alpha EEG band, a secondstimulation waveform corresponding to the beta 1 EEG band, and a thirdstimulation waveform corresponding to the beta 2 EEG band, each of thestimulation waveforms having an increasing modulation waveformfrequency. In such an example, the stimulation frequency will repeatedlyincrease in a nonlinear stepwise fashion. This stimulation signal couldfurther the reverse sequence of stimulation waveforms, each having adecreasing modulation waveform frequency. Alternatively, the stimulationsignal could repeat the sequence of stimulation waveforms, restartingwith stimulation having the lowest instantaneous frequency of the firststimulation waveform. In some embodiments, the instantaneous frequencyof the modulating waveform may vary linearly:

F _(mod) =F _(start)+(F _(finish) −F _(start))*(t/T _(duration))

Where F_(mod) is the instantaneous frequency, F_(start) is the frequencyat the beginning of the increasing or decreasing frequency interval,F_(finish) is the maximum frequency at the end of the increasing ordecreasing frequency interval, and T_(duration) is the duration overwhich the frequency changes linearly. In some embodiments, T_(duration)may be the duration of the increasing or decreasing frequency interval.In various embodiments, the instantaneous frequency of the modulatingwaveform may cease changing once t is greater than T_(duration).

In some embodiments, two or more waveforms may be combined to createstuffed stimulation waveform 702. For example, stuffed stimulationwaveform 702 may comprise a first waveform corresponding to a first EEGband mixed with a second waveform corresponding to a second EEG band. Insome aspects, stuffed stimulation waveform 702 may comprise one morewaveforms generated and provided for therapeutic stimulation in atemporally overlapping manner. For example, a predetermined gap mayseparate the beginning of the first waveform and the beginning of thesecond waveform. As an additional example, a predetermined gap mayseparate the end of the first waveform and the end of the secondwaveform. In some aspects one or more waveforms may be generatedsimultaneously. For example, the first waveform and the second waveformmay begin at the same time. As another example the first waveform andthe second waveform may end at the same time. In some embodiments, toalign the beginning and end of the one or more waveforms comprising astuffed stimulation waveform 702, the duration of at least one of theone or more waveforms may be scaled. For example the duration of atleast one of the increasing and decreasing frequency intervals in the atleast one of the one or more waveforms may be multiplied by a scalingfactor. In certain aspects multiple waveforms may be generated, mixed byan analog or digital mixer, and then provided for therapeuticstimulation. In various aspects, stuffed waveform 702 may be stored,retrieved, and then provided for therapeutic stimulation. In someaspects, stuffed waveform 702 may be generated by simultaneouslyproviding one or more waveforms through multiple speakers, withoutmixing at least one of the one or more waveforms. Likewise. and in thesame manner, in some embodiments one or more stimulation signals 700 maybe combined to create stuffed stimulation signals 700.

Exemplary Therapeutic Auditory Stimulation Protocol

Consistent with disclosed embodiments, therapeutic auditory stimulationmay be used to treat patients with autism spectrum disorders. In certainaspects, patients may receive a predetermined number of sessions oftherapeutic auditory stimulation. For example, patients may receivebetween 2 and 20 sessions of therapeutic auditory stimulation. As anadditional example, patients may receive between 8 and 14 sessions oftherapeutic auditory stimulation. Sessions may be approximately daily,weekly, bimonthly, or monthly, or a combination of such intervals. Forexample, a first session may be followed by another sessionapproximately a week later, which may be followed by another sessionapproximately a day, week, two weeks, or month later. In someembodiments, patients may receive therapeutic auditory stimulation solong as they continue to exhibit symptoms. In certain embodiments,patients may receive therapeutic auditory stimulation as a maintenancetherapy indefinitely.

In certain embodiments, patients may receive a predetermined stimulationsignal. In certain aspects, this stimulation signal may include threestimulation waveforms. In some aspects this stimulation signal mayinclude four stimulation waveforms. In some aspects this stimulationsignal may include more than four stimulation waveforms, such as sixstimulation waveforms. The duration of each stimulation waveform mayvary. For example, the duration of the stimulation waveforms may varybetween 1 and 10 minutes. The total duration of stimulation may varybetween 10 and 30 minutes. In some aspects, within each stimulationsignal, the stimulation waveforms may correspond to progressivelyincreasing EEG frequency bands. Exemplary stimulation signals areprovided in Table 3 below.

TABLE 3 Exemplary Stimulation Signals. Each row indicates an exemplarystimu- lation signal comprising either three or four stimulationwaveforms. These stimulation waveforms may correspond to EEG frequencybands, for example the second stimulation waveform in the third signalmay correspond to the Beta 2 EEG frequency band. The individual stimu-lation waveforms may comprise pairs of increasing and decreasingfrequency intervals as described above with regard to FIGS. 7A-7D. Theindividual stimulation waveforms may include a modulation wave- formthat varies nonlinearly between a maximum and minimum frequency value.In certain aspects, the maximum and minimum frequency values may be thevalues listed in Table 2. In some embodiments, the stimu- lation signalsin Table 3 may comprise a sequential course of thera- peutic auditorystimulation. For example, patients may receive stimulation signals 1-12in sequential sessions. Stimulation Stimulation Stimulation StimulationStimulation Signal Waveform 1 Waveform 2 Waveform 3 Waveform 4 1 AlphaBeta 1 Beta 2 None 2 Alpha Beta 1 Beta 2 Gamma 3 Beta 1 Beta 2 GammaNone 4 Alpha Beta 1 Beta 2 None 5 Theta Alpha Beta 1 Beta 2 6 ThetaAlpha Beta 1 None 7 Delta Theta Alpha Beta 1 8 Delta Theta Alpha None 9Theta Alpha Beta 1 None 10 Theta Alpha Beta 1 Beta 2 11 Alpha Beta 1Beta 2 Gamma 12 Beta 1 Beta 2 Gamma None

Therapeutic Auditory Stimulation—Case Studies

Beneficial results of simplified forms of therapeutic auditorystimulation have been observed in animals. For example, as reported in“Investigation of antidepressants activity of sound beats created withdifferent algorithms of modulation in comparison with antidepressants inforced swim test (FST) on rats,” cited above and hereby incorporated byreference in its entirety, therapeutic auditory stimulation has beenshown to provide benefits in an animal model of depression. In thisstudy, therapeutic auditory stimulation using an amplitude and frequencymodulated 1 kHz carrier wave reduced immobility and increased swimmingin rates during a forced swim test. These tests were conducted on 89healthy rats divided into eight groups. Three groups served as controls:one received no treatment (Group 1), one received an unmodulated 1 kHzcarrier wave (Group 2), and one received saline solution injections(Group 5). Two groups received auditory stimulation therapy consistingof amplitude and frequency modulated sounds at either 2-13 Hz (Group 3)or 13-55 Hz (Group 4). Three groups received known chemicalantidepressants (Group 6—Amitriptyline; Group 7—Mianserin, and Group8—Sertaline). As shown in FIG. 2C, the rats treated with the auditorystimulation therapy exhibited increased swimming and decreasedimmobility as compared to the intact control rats.

Therapeutic auditor stimulation consistent with the disclosedembodiments has also been shown to benefit human patients with anxiety,depression, and chronic pain. In one study, twenty-two patientssuffering from severe depression and chronic pain, and four patientssuffering from high anxiety received therapeutic auditory stimulation intwo sessions approximately every other day. The patients provided asubjective assessment of the therapy after every session and after twoweeks of treatment. Of the twenty-six patients, twenty-three experiencedsome reduction in symptoms. The four patients with high anxietyexperienced a marked reduction in anxiety. Of the twenty-two patientswith severe depression and chronic pain, nineteen experienced somereduction in symptoms.

Therapeutic auditory stimulation consistent with the disclosedembodiments has also been shown to benefit a patient diagnosed withAsperger's Syndrome. This patient received three sessions of therapeuticauditory stimulation a day for three days. The patient described areduction in stress and anxiety from the therapeutic auditorystimulation. This self-report was corroborated by reports from theparents, teachers, and counselor of the patient.

Five autistic patients received therapeutic auditory stimulationconsistent with disclosed embodiments. Pre-training baseline 19 channelEEG recordings were obtained prior to therapeutic auditory stimulation.Recorded EEG data was analyzed using quantitative topographic and LORETAtomographic analysis. Stimulation waveforms were chosen based on mostabnormal EEG frequency band and most deviant Z score LORETA voxel.Stimulation was provided for approximately 10 minutes through audiospeakers. Post-training baseline 19 channel EEG recordings were obtainedfollowing therapeutic auditory stimulation. Pre and post trainingcomparisons were performed using paired t-tests and Cohen's d for effectsizes. The results are given in Table 4 below.

TABLE 4 Results of Therapeutic Auditory Stimulation for Five AutisticPatients. The most deviant Brodmann area, as determined using LORETAEEG, is listed in the second column, while the most deviant EEGfrequency band is listed in the third column. The baseline Z scoreindicates the Z score of the most deviant voxel identified by LORETAEEG, while the Z score change towards normal indicates the change inthis Z score following therapeutic auditory stimulation. The P valueindicates the statistical significance of the change, while the effectsize indicates the clinical magnitude of the change. Most Most Z ScoreDeviant Deviant EEG Change Brodmann Frequency Baseline Z Toward AreaBand Score Normal P Value Effect Size Case 1 10 Right Delta +4.74 2.62 P< 0.00001 Very Large Case 2  2 Left Theta +6.12 1.88 P < 0.00001 VeryLarge Case 3 24 Left High Beta +4.33 1.59 P < 0.00001 Very Large Case 447 Right Delta +4.05 1.9 P < 0.00001 Very Large Case 5 23 Left Delta+5.77 2.14 P < 0.00001 Very Large

FIGS. 8A-8D depict the results of this intervention for Case 1. FIGS. 8Aand 8B depict four neuroimages of the patient's brain during acquisitionof the pre-therapy baseline EEG recording. As shown, the patient isexperiencing an abnormal area of activation, shown by 811, 813, 815, and817. FIGS. 8C and 8D depict the same four neuroimages of the patient'sbrain during acquisition of the post-therapy baseline EEG recording. Asshown, following the 10 minutes of therapeutic auditory stimulation, thepatient is no longer experiencing the abnormal activity depicted inFIGS. 8A and 8B. Similar results were seen with other cases in thestudy.

This study demonstrated that therapeutic auditory stimulation consistentwith disclosed embodiments was able to disentrain or dehabituateabnormal and deregulated neural network activity. Thus this therapeuticauditory stimulation could be used to normalize neural function, relievesymptoms and improve system adaptivity. Dynamic analyses of specificfrequency bands during stimulation also revealed frequency-band specificdisentrainment effects.

Additionally, thirty-five patients with autism, Asperger's, attentiondeficit disorder, and anxiety disorders are currently being treated withtherapeutic auditory stimulation as part of an ongoing clinical researchproject. Many of these patients have demonstrated a reduction insymptoms and noticeable improvements in functioning during treatment.

The foregoing description of the inventions, along with their associatedembodiments, has been presented for purposes of illustration only. It isnot exhaustive and does not limit the inventions to the precise formdisclosed. Those skilled in the art will appreciate from the foregoingdescription that modifications and variations are possible in light ofthe above teachings or may be acquired from practicing the inventions.For example, the steps described need not be performed in the samesequence discussed or with the same degree of separation. Likewisevarious steps may be omitted, repeated, or combined, as necessary, toachieve the same or similar objectives. Similarly, the systems describedneed not necessarily include all parts described in the embodiments, andmay also include other parts not describe in the embodiments.Accordingly, the inventions are not limited to the above-describedembodiments, but instead are defined by the appended claims in light oftheir full scope of equivalents.

What is claimed is:
 1. A device for providing therapeutic auditory stimulation comprising: a processor and a non-transitory memory containing instructions that when executed by the processor cause the device to generate one or more stimulation waveforms, the stimulation waveforms: corresponding to electroencephalographic (EEG) frequency bands, and comprising audible carrier frequencies modulated by signals with frequencies that vary non-linearly with time; and means for providing one or more of the stimulation waveforms to a patient as therapeutic auditory stimulation.
 2. The device of claim 1, wherein the EEG frequency bands comprise a low-frequency band and a high-frequency band, and the stimulation waveform corresponding to the low-frequency band is provided before the stimulation frequency corresponding to the high-frequency band.
 3. The device of claim 1, wherein the EEG frequency bands comprise a low-frequency band and a high-frequency band, and the stimulation waveform corresponding to the high-frequency band is provided before the stimulation frequency corresponding to the low-frequency band.
 4. The device of claim 1, wherein the frequencies increase exponentially from the beginning to the end of each stimulation waveform.
 5. The device of claim 1, wherein the stimulation waveforms comprise pairs of frequency intervals, the pairs including increasing frequency intervals and decreasing frequency intervals, the frequencies increasing exponentially during the increasing frequency intervals and decreasing exponentially during the decreasing frequency intervals.
 6. The device of claim 5, wherein the durations of the pairs vary non-linearly.
 7. The device of claim 5, wherein the durations of the decreasing frequency intervals exceed the durations of the increasing frequency intervals.
 8. The device of claim 5, wherein the durations of the increasing and decreasing frequency intervals are approximately related by a constant multiple.
 9. The device of claim 8, wherein the constant multiple is the golden ratio.
 10. The device of claim 1, wherein the EEG frequency bands are selected from the group consisting of the delta, theta, alpha, beta 1, beta 2, and gamma electroencephalographic frequency bands.
 11. A system for providing therapeutic auditory stimulation comprising: a diagnostic unit that computes an EEG spectral density of a patient and a heart rate spectral density of the patient and provides values for one or more EEG frequency bands and one or more heart rate frequency bands; a therapy unit that generates, based on the provided values, one or more stimulation waveforms corresponding to one or more of the EEG frequency bands and provides the stimulation waveforms for therapeutic auditory stimulation.
 12. The system of claim 11, wherein the diagnostic unit includes an electroencephalograph comprising two or more occipital electrodes.
 13. The system of claim 11, wherein the diagnostic unit calculates the sympathovagal balance of the patient.
 14. The system of claim 11, wherein the stimulation waveforms comprise audible carrier frequencies modulated by signals with frequencies that vary exponentially with time.
 15. The system of claim 14, wherein the frequencies increase exponentially from the beginning to the end of each stimulation waveform.
 16. The system of claim 14, wherein the stimulation waveforms comprise pairs of frequency intervals, the pairs including increasing frequency intervals and decreasing frequency intervals, the frequencies increasing exponentially during the increasing frequency intervals and decreasing exponentially during the decreasing frequency intervals.
 17. The system of claim 16, wherein the durations of the pairs vary non-linearly.
 18. The system of claim 16, wherein durations of the decreasing frequency intervals exceed durations of the increasing frequency intervals.
 19. The system of claim 16, wherein the durations of frequency intervals are approximately related by a constant multiple.
 20. The system of claim 19, wherein the constant multiple is the golden ratio.
 21. The system of claim 11, wherein the EEG frequency bands comprise the delta, theta, alpha, beta 1, beta 2, and gamma EEG frequency bands.
 22. The system of claim 11, wherein the stimulation waveforms are generated remotely from the therapeutic auditory stimulation.
 23. The system of claim 11, wherein at least one of the stimulation waveforms is provided for therapeutic auditory stimulation telephonically.
 24. A method for therapeutic auditory stimulation, comprising: receiving an indication of an abnormal physiological state of a patient; generating a first stimulation waveform based on the indication, the first stimulation waveform corresponding to a first EEG frequency band and comprising an audible carrier frequency modulated by a first signal with an exponentially varying frequency; and providing the first stimulation waveform for first therapeutic auditory stimulation.
 25. The method of claim 24, wherein a maximum frequency of the first signal corresponds to a maximum frequency associated with the first EEG frequency band.
 26. The method of claim 24, further comprising generating a second stimulation waveform based on the indication, the second waveform corresponding to a second EEG frequency band and comprising the audible carrier frequency modulated by a second signal with an exponentially varying frequency; and providing the second stimulation waveform for second therapeutic auditory stimulation.
 27. The method of claim 26, wherein the first EEG frequency band is less than the second EEG frequency band and the first therapeutic auditory stimulation is provided before the second therapeutic auditory stimulation.
 28. The method of claim 26, wherein the first EEG frequency band is greater than the second EEG frequency band and the first therapeutic auditory stimulation is provided before the second therapeutic auditory stimulation.
 29. The method of claim 24, wherein the first signal comprises pairs of frequency intervals, the pairs including increasing frequency intervals and decreasing frequency intervals, a frequency of the first signal increasing exponentially during the increasing frequency intervals and decreasing exponentially during the decreasing frequency intervals.
 30. The method of claim 29, wherein the durations of the pairs vary non-linearly.
 31. The method of claim 29, wherein the durations of the decreasing frequency intervals exceeds the durations of the increasing frequency intervals.
 32. The method of claim 29, wherein the durations of the increasing frequency intervals and the decreasing frequency intervals depend on the first EEG frequency band.
 33. The method of claim 29, wherein the durations of the increasing frequency intervals and the durations of the decreasing frequency intervals are approximately related by a constant multiple.
 34. The method of claim 24, wherein the first EEG frequency band is selected from the group consisting of the delta, theta, alpha, beta 1, beta 2, and gamma EEG frequency bands.
 35. The method of claim 24, wherein the indication is based on electroencephalography and a sympathovagal balance measurement of the patient.
 36. The method of claim 35, wherein the indication is based on the relative amplitudes of one or more EEG frequency bands.
 37. The method of claim 24, wherein the indication is based on a questionnaire result.
 38. The method of claim 24, wherein the first stimulation waveform is generated remotely from the first therapeutic auditory stimulation.
 39. The method of claim 24, wherein the first stimulation waveform is provided for the first therapeutic auditory stimulation telephonically.
 40. The method of claim 24, wherein the first stimulation waveform is provided for the first therapeutic auditory stimulation on a computer-readable medium.
 41. A method of therapeutic auditory stimulation, comprising: measuring, using a portable electroencephalograph, a sympathovagal balance of a patient and contributions from one or more EEG frequency bands to an EEG of the patient; generating, using a processor, a train of stimulation waveforms based on an indication of an abnormal physiological state of the patient, one of the stimulation waveforms corresponding to an EEG frequency band and comprising an audible carrier frequency modulated by a signal including frequency intervals comprising: increasing frequency intervals during which the frequency of the signal increases exponentially, decreasing frequency intervals during which the frequency of the signal decreases exponentially, and wherein the durations of the increasing frequency intervals and the decreasing frequency intervals vary and depend on the EEG frequency band corresponding to the stimulation waveform; and providing, using the processor, the stimulation waveforms to an audio speaker for generating therapeutic auditory stimulation for the patient.
 42. The method of claim 41, wherein the durations of frequency intervals are approximately related by a constant multiple.
 43. The method of claim 42, wherein the constant multiple is the golden ratio.
 44. The method of claim 41, wherein the EEG frequency bands comprise the delta, theta, alpha, beta 1, beta 2, and gamma EEG frequency bands.
 45. The method of claim 41, wherein the train of stimulation waveforms is generated remotely from the audio speaker.
 46. The method of claim 45, further comprising storing, using the processor, the train of stimulation waveforms in a non-transitory memory before providing the stimulation waveforms to the audio speaker.
 47. The method of claim 46, wherein a telephone comprises the audio speaker.
 48. A non-transitory computer-readable medium comprising instructions that, when executed by a processor, cause a computer to perform the operations comprising: generating, using the processor, a train of stimulation waveforms based on an indication of an abnormal physiological state of a patient, one of the stimulation waveforms corresponding to an EEG frequency band and comprising an audible carrier frequency modulated by a signal including frequency intervals comprising: increasing frequency intervals during which the frequency of the signal increases exponentially, decreasing frequency intervals during which the frequency of the signal decreases exponentially, and wherein the durations of the frequency intervals are approximately related by a constant multiple; and providing, using the processor, the stimulation waveforms to an audio speaker for generating therapeutic auditory stimulation for the patient.
 49. The non-transitory computer-readable medium of claim 48, wherein the constant multiple is the golden ratio.
 50. The non-transitory computer-readable medium of claim 48, wherein the EEG frequency bands comprise the delta, theta, alpha, beta 1, beta 2, and gamma EEG frequency bands. 